Mechanisms underlying nutrient induced intestinal cholecystokinin (CCK) secretion are not completely described. Research from several laboratories show that intestinal CCK secretion is stimulated by luminal CCK releasing factors. Apelin is the newest member of a family of peptides shown to signal intestinal CCK secretion by an action from within the intestinal lumen. Apelin is unique in that gastric apelin is produced in stomach exocrine and endocrine cells implying that apelin acts by endocrine as well as luminal routes to cause CCK secretion. Another unique feature is that apelin is secreted into the stomach lumen rather than the small intestinal lumen. This proposal examines the hypothesis that gastric apelin plays a role as a physiological regulator of intestinal CCK secretion. To test this hypothesis studies are proposed to define the importance of luminal and systemic apelin in the physiological regulation of CCK secretion using surgically prepared stomach and intestinal perfusion rat models. Our Specific Aims are: Aim 1. To test the hypothesis that dietary nutrients activate secretion of gastric apelin. Aim 2. To test the hypothesis that gastric apelin plays a role in the regulation of intestinal cholecystokinin (CCK) secretion. Preliminary data show abundant apelin-positive cells in the stomach epithelium, that the gut lumen and systemic circulation contain apelin, that apelin stimulates CCK secretion in vitro and in vivo in the rat, and that luminal immunoneutralization of apelin decreases nutrient-induced CCK secretion. In Aim 1 we expect to show that gastric apelin is produced in at least two different gastric cell types, to define nutrient-induced apelin secretion into plasma and luminal compartments, and show that ligands which activate parietal cell secretion simultaneously cause apelin release into the gastric lumen. In Aim 2 we will define the importance of gastric apelin in nutrient-induced CCK secretion using immunoneutralization. It is important to understand mechanisms that signal CCK secretion in view of the roles CCK may play in various digestive diseases and appetite disorders. A better appreciation of regulation of CCK secretion will help in understanding the pathophysiology of these disease processes and give insight into new clinical therapies.